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Project 1 - Molecular Genetics Of Non-Coding RNA

Working with the other members of the CLL Research Consortium, we have discovered that most of CLLs are initiated by the loss of miR-15/16, the first evidence of the role of alterations in non-coding genes in cancer. Following this discovery, we found that miR-15/16 target BCL2, a gene we discovered in 1984. Thus, the loss of these two microRNAs causes the overexpression of BCL2, which is observed in CLL B cells CLLs. We also discovered that the B cells from patients with aggressive CLL overexpress TCL1, a gene we discovered in 1993. We established the Eμ-TCL1 mouse model that develops only the aggressive form of CLL and is currently used by many laboratories around the world to study tumor/microenvironment interactions and drug sensitivity and resistance in CLL.

Our laboratory discovered that the overexpression of TCL1 is caused, for the most part, by the loss of microRNAs that target it, and that Tcl1, an activator of AKT1, is a strong inhibitor of the de novo DNA methyltransferases, Dnmt3A and 3B. Recently, frequent mutations in Dnmt3A have been discovered in AML.

Recently, by investigating miR-3676, which is co-deleted with TP53 at 17p13 in CLL and targets the 3’ UTR of TCL1, we discovered that miR-3676 is not a microRNA, although it can function also as one, but represents the first member of a new class of short non-coding RNAs, tsRNAs, that derives from the 3’ end of precursor tRNA, following cleavage by nuclease Z. We also discovered that the tsRNAs bind PiwiL2 and contribute to the Piwi pathway of gene silencing.

We hypothesize that in order to avoid drug resistance during CLL treatment, we can take advantage of microRNA dysregulation to identify novel targets for treatment. Since microRNAs have multiple targets, we investigated additional targets of miR-15/16. Our studies have indicated that ROR1, an orphan receptor expressed on CLL cells, but not on normal lymphoid cells, is negatively regulated by miR-15/16 and is coexpressed with BCL2, in cells that have lost miR-15/16.

We thus propose that CLL patients could be treated with combination therapy such as venetoclax and anti-ROR1 monoclonal antibodies to avoid drug resistance.